This invention relates to intermediates useful in the preparation of prostaglandins and to a process for preparing them.
Each of the known prostaglandins is a derivative of prostanoic acid which has the following structure and atom numbering: ##SPC5##
A systematic name for prostanoic acid is 7-[(2.beta.-octyl)cyclopent-1.alpha.-yl]heptanoic acid.
Prostaglandin E.sub.2, "PGE.sub.2 ", has the following structure: ##SPC6##
Prostaglandin F.sub.2.sub..alpha., "PGF.sub.2.sub..alpha. ", has the following structure: ##SPC7##
The prostaglandin formulas mentioned above each have several centers of asymmetry. Each formula represents a molecule of the particular optically active form of the prostaglandin obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, and human seminal plasma, or by reduction or dehydration of a prostaglandin so obtained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. The mirror image of each formula represents a molecule of the other enantiomeric form of that prostaglandin. The racemic form of the prostaglandins consists of equal numbers of two types of molecules, one represented by one of the above formulas and the other represented by the mirror image of that formula. Thus, both formulas are needed to define a racemic prostaglandin. See Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.
In the formulas above, as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e. above the plane of the cyclopentane ring. In the formulas above, the hydroxyl attachment to carbon 15 is in the alpha configuration, as indicated by the broken line. In formulas below, this convention is also used for intermediates having hydroxyl substituted at the corresponding position on the side chain. A wavy line .about. indicates optional attachment to carbon 15 in either alpha or beta configuration.
The various optically active and racemic prostaglandins and their alkyl esters are useful for various pharmacological purposes. With particular regard to PGF.sub.2.sub..alpha. see, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein, Wiqvist et al., The Lancet, 889 (1970), and Karim et al., J. Obstet. Gynaec. Brit. Cwlth., 76, 769 (1969). As to the other prostaglandins, see, for example Ramwell et al., Nature 221, 1251 (1969).
Previously, the preparation of an intermediate bicyclic lactone ketone of the formula ##SPC8##
wherein R.sub.4 is acetyl was reported by E. J. Corey et al., J. Am. Chem. Soc. 91, 5675 (1969), and later disclosed in an optically active form by E. J. Corey et al., J. Am. Chem. Soc. 92, 397 (1970). Conversion of this intermediate to PGE.sub.2 and PGF.sub.2.sub..alpha., either in racemic (dl-) or optically active form, was disclosed in those publications. For that compound wherein R.sub.4 is benzoyl see U.S. Pat. No. 3,778,450.
Related compounds of the formula ##SPC9##
wherein R.sub.4 is acetyl or benzoyl have been disclosed as follows:
1. wherein G is alkyl of one to 10 carbon atoms, inclusive, substituted with zero to 3 fluoro, German Offenlegungsschrift No. 2,406,287, Derwent Farmdoc 60337V; PA1 2. wherein G is ##EQU2## wherein R.sub.5 and R.sub.6 are hydrogen, methyl, or ethyl, provided that at least one of R.sub.5 and R.sub.6 is not hydrogen, German Offenlegungsschrift No. 2,217,044, Derwent Farmdoc 71483T; PA1 3. wherein G is ##EQU3## wherein C.sub.n H.sub.2n is alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive, in the chain between --CFR.sub.7 -- and terminal methyl and wherein R.sub.7 is hydrogen, methyl, ethyl, or fluoro, Netherlands Application No. 7305817, Derwent Farmdoc 69717U; and PA1 4. wherein G is ##SPC10## PA1 wherein R.sub.8 and R.sub.9 are hydrogen, methyl, or ethyl, wherein T is alkyl of one to 3 carbon atoms, inclusive, fluoro, chloro, trifluoro, or --OR.sub.10 wherein R.sub.10 is alkyl of 1 to 3 carbon atoms, inclusive, and wherein s is zero, 1, 2, or 3, with the proviso that not more than two T's are other than alkyl, Netherlands Application No. 7306462, Derwent Farmdoc 73279U.
Also disclosed is a compound of the formula: ##SPC11##
wherein Ac represents an acyl radical, either acetyl or p-phenylbenzoyl, X is an alkylene radical of 2 or 3 carbon atoms, optionally bearing as substituent or substituents one or two alkyl radicals each of 1 to 4 carbon atoms, and R.sub.11 is an aryl or thienyl radical, which is unsubstituted or which is substituted by halogen atoms, nitro radicals, alkyl, halogenoalkyl or alkoxy radicals each of 1 to 3 carbon atoms or dialkylamino radicals wherein each alkyl is of 1 to 3 carbon atoms, Netherlands Application No. 7209817, Derwent Farmdoc 5789U.
A related disclosed compound is ##SPC12##
wherein THP is tetrahydropyranyl, useful in the synthesis of PGF.sub.3.sub..alpha., E. J. Corey et al. J. Am. Chem. Soc. 93, 1490 (1971).